PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements.

18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.     

Treatment of premature ejaculation: New drugs and treatment strategies

This review discusses treatment options for men with premature ejaculation (PE), a common sexual dysfunction characterized by short ejaculatory latency, decreased sexual satisfaction, and distress. For a number of reasons, including embarrassment and the belief that PE is a normal part of aging, that it has no effective treatment, or that it will resolve itself, few men with PE seek treatment. Although several treatment options exist (eg, behavioral, cognitive, and sex therapy methods; desensitizing drugs; off-label use of antidepressants, phosphodiesterase type 5 inhibitors, or à-blockers), the majority of men with PE are not satisfied with their results. New pharmacologic drugs develped specifically for the treatment of PE are undergoing evaluation in clinical trials. For example, recent clinical research studies have revealed on-demand administration of one such drug, dapoxetine, which achieved significant improvements in ejaculatory latency, control over ejaculation, and satisfaction with sexual intercourse. In addition, partners of men who received dapoxetine likewise reported improved satisfaction with sexual intercourse. Future studies may reveal that integration of pharmacologic drugs with psychologic and/or behavioral therapy techniques may be the optimal approach to the management of PE. PE is a treatable condition, and new drugs in development may provide benefits over those available.     

Patient-proxy response comparability on measures of patient health and functional status

The present study evaluates the response comparability between 361 elderly hip fracture patients admitted from the community to seven Baltimore area hospitals between 1984 and 1986 and interviewer selected proxies on items pertaining to patients' pre-fracture health and functional status. Agreement across items ranges from very poor to good and varies with respect to the health or functional area assessed. Proxies tend to overestimate patient disability relative to the patients themselves, especially with regard to capacity to perform instrumental activities of daily living. Although proxies who report the greatest contact with patients respond most comparably to the patients, when they do disagree, proxies with the greatest patient contact tend to overestimate patient disability. The authors suggest that attention to item construction and phrasing may improve response comparability.     

The morbidity and mortality conference: the delicate nature of learning from error.

The morbidity and mortality conference (M&MC) appears to have sprung from the efforts of physicians to improve practice through the examination of medical errors and bad outcomes. The modern M&MC has had limited examination (and almost none outside surgery and anesthesia), but may be straying from the precepts from which it evolved. Learning from one's errors is important, but confronting them is difficult and is particularly delicate when done in conference. If the effort is successful, it can serve as a model. If unsuccessful, it can instead convey the lesson that attempting to learn from error is at best unproductive and at worst unpleasant. Thus, the M&MC is a double-edged sword, and particular attention should be given to the way that it is conducted. The authors review the historical roots and current literature on the M&MC, discusses relevant literature on medical error, and offers a definition, guiding principles, and a set of guidelines for a modern internal medicine M&MC. The ideas are presented not as a blueprint, but rather to stimulate a debate on the merits of establishing a framework for a working model, in order to refocus on the tradition of self-analysis and critical thinking in a manner that is productive for all participants.     

Adenoviral vectors do not induce, inhibit, or potentiate human platelet aggregation.

Adenoviruses are commonly used as vectors in human clinical gene therapy trials. High doses of intravenous adenovirus vectors have been associated with development of thrombocytopenia of undetermined origin. Viral internalization requires the presence cell surface integrins, alpha(v)beta(3) or alpha(v)beta(5), that can blind ligands with a arginine-glycine-aspartic acid (RGD) sequence. This sequence is found in the adenovirus penton base. Platelets express the alpha(v)beta(3) integrin and other integrins that bind the RGD sequence of ligands such as fibrinogen, laminin, vitronectin, and von Willebrand factor (vWF). Platelet aggregation is mediated, in part, by the binding of the RGD sequence of fibrinogen to a platelet surface integrin, glycoprotein IIb/IIIa (GP IIb/IIIa). We investigated whether adenovirus particles could interfere with or potentiate agonist-induced platelet aggregation. Incubation of platelet-rich plasma with adenovirus under stirred conditions did not promote spontaneous aggregation. The addition of physiological platelet agonists, ADP, collagen, or epinephrine, induced platelet aggregation. However, the presence of adenovirus in a wide range of concentrations did not inhibit or potentiate agonist-induced aggregation. These results suggest that the adenovirus-associated thrombocytopenia observed in vivo is independent of a direct effect of the virus on platelet aggregation.     

Reengineering transfusion and cellular therapy processes hospitalwide: ensuring the safe utilization of blood products

Efforts to make blood transfusion as safe as possible have focused on making the blood in the bag as disease-free as possible. The results have been dramatic, and the costs have been correspondingly high. Although blood services will have to continue to deal with emerging pathogens, efforts to reduce the transfusion of infectious agents presently posing a risk will require high incremental costs and result in only improvements of a small magnitude.
The other aspect of safe blood transfusion, the actual transfusion process performed primarily in hospitals, has been accorded considerably less interest. We should turn our attention to enhancing overall blood safety by focusing on improving the process of blood transfusion. Errors involving patient, specimen, and blood product identification put transfused patients at risk, increasing the mortality risk for some. Solutions that could improve the transfusion process are discussed as a focus of this article.     

Basic protein enhances the incorporation of DNA into lipid vesicles: model for the formation of primordial cells.

DNA can be encapsulated into lipid vesicles formed by sonication. The presence of a basic protein, lysozyme, enhances the incorporation 100-fold above the level expected by random trapping. This is demonstrated by the ability of the lipid vesicles to protect DNA from digestion with DNase. Such an enhancement of nuclei acid incorporation into vesicles by basic polypeptides and the sharply increased concentration of these macromolecules in the internal volume may have been advantageous in prebiotic evolution.     

Mechanics and function in heart morphogenesis.

For years, biomechanical engineers have studied the physical forces involved in morphogenesis of the heart. In a parallel stream of research, molecular and developmental biologists have sought to identify the molecular pathways responsible for embryonic heart development. Recently, several studies have shown that these two avenues of research should be integrated to explain how genes expressed in the heart regulate early heart function and affect physical morphogenetic steps, as well as to conversely show how early heart function affects the expression of genes required for morphogenesis. This review combines the perspectives of biomechanical engineering and developmental biology to lay out an integrated view of the role of mechanical forces in heart development.